An Improved Synthesis of m-Hydroxymexiletine, a Potent Mexiletine Metabolite

Abstract

m-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid.

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

“…This work is an extension of our previuos work, in which we reported the synthesis of racemic MHM [17]. MHM is a minor metabolite of mexiletine, which is active on voltage-dependent sodium channels: in particular, it is equipotent to mexiletine on skeletal muscle channels and 2-fold more potent of the parent compound on the cardiac ones [15][16][17]. All the intermediates for the synthesis of (R)and (S)-MHM were fully characterized.…”

“…The synthetic sequence to (R)-and (S)-MHM (Scheme 1) exploits the one previously reported for the racemate [17]. Homochiral aminopropanols 1 were protected with phthalic anhydride in quantitative yield to give the phthalimido alcohols 2 which were reacted with 4-chloro-2,6dimethylphenol under Mitsunobu conditions [15,24,25].…”

“…Thus, with the aim of finding a substitute for mexiletine, which could show the same activity but lower side effects, we proposed a metabolite switch from mexiletine to m-hydroxymexiletine (MHM, 3-(2-aminopropoxy)-2,4dimethylphenol, Fig. 1) [15][16][17]. MHM is a minor metabolite of mexiletine, which in humans accounts for approximately 2% of an administered oral dose of mexiletine, but its great importance is due to the fact that it is equipotent to mexiletine on voltage-gated skeletal muscle sodium channels and even 2-fold more potent than the parent compound on the cardiac ones [15][16][17].…”

“…1) [15][16][17]. MHM is a minor metabolite of mexiletine, which in humans accounts for approximately 2% of an administered oral dose of mexiletine, but its great importance is due to the fact that it is equipotent to mexiletine on voltage-gated skeletal muscle sodium channels and even 2-fold more potent than the parent compound on the cardiac ones [15][16][17]. Herein, we propose a synthetic route to (R)-and (S)-MHM, which might feed studies in view of a chiral switch from MHM to one of its enantiomers provided that they show differences in pharmacodynamics and/or pharmacokinetics.…”

Synthesis and Antimicrobial Evaluation of a New Series of N‐1,3‐Benzothiazol‐2‐ylbenzamides

“…In particular, compound 3i was the most potent of the series (MIC: 8 g/mL) and the most promising compound, while the other showed an MIC value of 32 g/mL. [38][39][40][41]. TLC analyses were performed on precoated silica gel on aluminum sheets (Kieselgel 60 F 254 , Merck).…”